Characteristics of CD4-1 gene and its immune responses against Aeromonas veronii infection by activating NF-κB signaling in Qihe crucian carp Carassius auratus.

CD4-1 found in bony fish contains four extracellular immunoglobulin (Ig)-like domains similar to that of mammalian CD4, which is crucial for the activation of CD4+ helper T-cell. However, there is limited knowledge regarding the molecular markers, immune functions and regulation mechanism of CD4-1 in teleosts due to their vast diversity. In this study, we cloned and characterized two isoforms of Qihe crucian carp CD4-1, designated as CaCD4-1.1 and CaCD4-1.2. We further explored their expression responses upon stimulation with Aeromonas veronii, and the regulation of their immune responses against A. veronii by NF-κB. The ORF of CaCD4-1.1 and CaCD4-1.2 cDNA encoded 477 and 466 amino acids, respectively. Both proteins contained seven conserved cysteine residues in the extracellular domain, and a CCC motif in their cytoplasm, respectively. However, CaCD4-1.1 exhibited a relatively limited similarity with CaCD4-1.2 in the ectodomain. The quantitative real-time polymerase chain reaction (qRT-PCR) analysis revealed that the mRNA expression of CaCD4-1.1 and CaCD4-1.2 exhibited differential constitutive expression across all examined tissues. Furthermore, the expression level of CD4-1.2 was higher than that of CD4-1.1 in the gills, head kidney, and spleen of Qihe crucian carp subjected to A. veronii challenge, while it was lower in the trunk kidney. Inhibition of NF-κB activity resulted in a decrease in the expression levels of CD4-1.1 and CD4-1.2 mRNA in the gill, while inducing an increase in expression levels in the spleen, in accordance with the observed ultrastructural changes in both organs. Interestingly, the impact of NF-κB on the mRNA expression level of CD4-1.1 appears to be stronger than that of CD4-1.2. Our results suggest that CaCD4-1.1 and CaCD4-1.2 could be expressed on T cells and antigen-sampling cells that exhibit similar characteristics to mammalian M cells, respectively, and differentially regulated by NF-κB in adaptive immune responses against bacterial infection. This research contributes to a better understanding of the crucial role of CD4-1 in the immune response of Qihe crucian carp and provide novel insights for the prevention and treatment of fish diseases in aquaculture.

Human mpox: Biology, epidemiology, therapeutic options, and development of small molecule inhibitors.

Although monkeypox (mpox) has been endemic in Western and Central Africa for 50 years, it has not received sufficient prophylactic and therapeutical attention to avoid evolving into an epidemic. From January 2022 to January 2023, more than 84,000 of mpox cases were reported from 110 countries worldwide. Case numbers appear to be rising every day, making mpox an increasing global public health threat for the foreseeable future. In this perspective, we review the known biology and epidemiology of mpox virus, together with the latest therapeutic options available for mpox treatment. Further, small molecule inhibitors against mpox virus and the future directions in this field are discussed as well.

Microfracture technique combined with mesenchymal stem cells inducer represses miR-708-5p to target special at-rich sequence-binding protein 2 to drive cartilage repair and regeneration in rabbit knee osteoarthritis.

Knee osteoarthritis (KOA) is a degenerative joint illness which leads to knee pain and functional limitation. In this study, we combined microfracture surgery with kartogenin (KGN), a small bioactive molecule used to promote the differentiation of mesenchymal stem cells (MSCs), and explored its impact on cartilage repair and possible latent mechanisms of action. The research offers a brand-new idea for the clinical cure of KOA. The microfracture technique in combination with KNG treatment was performed on a rabbit model of KOA. Animal behaviour was evaluated after the intra-articular injection of miR-708-5p and Special AT-rich sequence binding protein 2 (SATB2) lentiviruses. Later, the expression of the tumour necrosis factor α (TNF-α) and interleukin- 1 (IL-1), the pathology of synovial tissue and cartilage tissue, and the positive cartilage type II collagen, MMP-1, MMP-3 and TIMP-1 were detected. Finally, a luciferase assay was conducted to verify the interaction of miR-708-5p and SATB2. Our results showed that miR-708-5p was elevated in the rabbit KOA model; however, the expression of SATB2 was reduced. Meanwhile, the microfracture technology combined with MSCs inducer KGN drove cartilage repair and regeneration in rabbit KOA by repressing the miR-708-5p expression. We also found that miR-708-5p directly targeted the SATB2 mRNA to regulate its expression. Furthermore, our data urged that elevating miR-708-5p or restraining SATB2 may reverse the therapeutic effect of the microfracture technique combined with MSCs inducer on rabbit KOA. Microfracture technique combined with MSCs inducer represses miR-708-5p to target SATB2 to drive cartilage repair and regeneration in rabbit KOA. This indicates that the microfracture technique combined with MSCs inducers is supposed to be an effective latent method for osteoarthritis cure.

Long-term cardiovascular outcomes of biodegradable polymer drug eluting stents in patients with diabetes versus non-diabetes mellitus: a meta-analysis.

BACKGROUND: Today, diabetes mellitus (DM) has become a worldwide concern. DM is a major risk factor for the development of cardiovascular diseases (CVD). Eligible patients with CVD are treated invasively by percutaneous coronary intervention (PCI) whereby a stent is implanted inside the coronary vessel with the particular lesion to allow sufficient blood flow. Newer scientific research have shown that even though associated with a lower rate of re-stenosis, first-generation drug eluting stents (DES) were associated with a higher rate of late stent thrombosis. Recently, newer stents, namely biodegradable polymer DES (BP-DES) have been developed to overcome the safety issues of earlier generation DES. In this analysis we aimed to systematically compare the long term (≥ 12 months) adverse cardiovascular outcomes observed in DM versus non-DM patients who were implanted with BP-DES. METHODS: Cochrane central, MEDLINE (Subset PubMed), EMBASE, Web of Science, http://www. CLINICALTRIALS: gov and Google scholar were searched for relevant publications involving BP-DES in patients with DM versus non-DM and their associated adverse cardiovascular outcomes. The mean follow-up time period ranged from 12 to 120 months. Data analysis was carried out with the latest version of the RevMan software (version 5.4). Based on the Mantel-Haenszel test, risk ratios (RR) with 95% confidence intervals (CI) were calculated and used to represent the results following analysis. RESULTS: Seven (7) studies with a total number of 10,246 participants were included in this analysis. Stents which were implanted during PCI were BP-DES. Participants were enrolled from the year 2006 to 2013. Our current results showed that in patients who were implanted with BP-DES, the risks of major adverse cardiac events (RR: 1.30, 95% CI: 1.18-1.43; P = 0.00001), myocardial infarction (RR: 1.48, 95% CI: 1.14-1.93; P = 0.003), all-cause mortality (RR: 1.70, 95% CI: 1.29-2.23; P = 0.0002), cardiac death (RR: 1.93, 95% CI: 1.28-2.93; P = 0.002), target vessel revascularization (RR: 1.35, 95% CI: 1.03-1.77; P = 0.03), target lesion revascularization (RR: 1.28, 95% CI: 1.07-1.54; P = 0.007) and target lesion failure (RR: 1.79, 95% CI: 1.52-2.12; P = 0.00001) were significantly higher in the DM group. Definite and probable stent thrombosis (RR: 1.80, 95% CI: 1.28-2.55; P = 0.0009) were also significantly higher in the DM group. CONCLUSIONS: Diabetes mellitus was an independent risk factor associated with long term adverse cardiovascular outcomes following PCI with BP-DES.

Characterization of CD3γ/δ gene and its immune response in Qihe crucian carp Carassius auratus after challenged by Aeromonas veronii and Poly(I:C).

CD3γ/δ found in non-mammalian vertebrates is a CD3 homolog with structural characteristics similar to both mammalian CD3γ and CD3δ, and plays important roles in T cell recognization and immune response in fish. In this study, the full-length of CD3γ/δ from Qihe crucian carp (named CaCD3γ/δ) was cloned and characterized, then the expression response profiles and potential immune functions was explored after Aeromonas veronii and Poly(I:C) challenge. The results showed that the full-length of CaCD3γ/δ was 819 bp including a 5'-UTR of 141 bp, a 3'-UTR of 168 bp, and an ORF of 510 bp encoding a putative 169-aa protein with an estimated MW of 18.71 kD and a theoretical pI of 8.77. The protein sequence of CaCD3γ/δ contained a Leu-Leu and a CXXXC motif in the extracellular domain, and an ITAM and a Leu-Ile motif in the cytoplasm, and a residue of Asn in the transmembrane. CaCD3γ/δ was constitutively expressed in the spleen, liver, gill, and blood of Qihe crucian carp. After the carp were challenged with Poly(I:C) and Aeromonas veronii, the mRNA expression levels of CaCD3γ/δ were significantly changed in the spleen, head kidney, intestine and gill, according to the results of qPCR. However, compared with A. veronii, Poly(I:C) challenge can rapidly induce the CaCD3γ/δ expression levels in head kidney, intestine and spleen, which suggested CaCD3γ/δ may be differentially modulated by different pathogens. Moreover, the results of immunohistochemical analysis showed that the CaCD3γ/δ+ secreted cells in the spleen and gills of Qihe crucian were increased after challenged with Poly(I:C), as well as the spleen challenged with A. veronii, but at different levels. Combined with the fact that vascular congestion, necrosis of parenchymal cells, and inflammatory cells including lymphocytes infiltration were also observed in the gill and spleen of Qihe crucian carp treated with A. veronii and Poly(I:C) revealed by pathological analysis, it was predicted that CaCD3γ/δ+ T lymphocytes may participated in the immune response against pathogens. This study will contribute to understand the important role of CaCD3γ/δ+ T lymphocytes in the immune response of Qihe crucian carp, and provide new insights for the prevention and treatment of the diseases of Qihe crucian carp.

Discovery of chiral 1,4-diarylazetidin-2-one-based hydroxamic acid derivatives as novel tubulin polymerization inhibitors with histone deacetylase inhibitory activity.

Tubulin and histone deacetylase have been clinically proven as promising targets for cancer therapy. Herein, we describe the design and synthesis of chiral 1,4-diarylazetidin-2-one-based hydroxamic acids as novel tubulin/HDAC dual inhibitors. Among them, compound 12a was validated to effectively disrupt tubulin polymerization, and exhibited potent HDAC1/8 inhibitory activities. Meanwhile, 12a showed good antiproliferative activities against four tumor cell lines. Further studies showed 12a works through blocking cellular cycle, inducing apoptosis and inhibiting colony formation. In addition, 12a has suitable physicochemical properties and high liver microsomal metabolic stability. Importantly, compound 12a was found to exhibit significant antitumor efficacy in vivo, thus warranting it as a promising tubulin/HDAC dual inhibitor for further development.

Diagnostic Value of Synovial Fluid Biomarkers for Periprosthetic Joint Infection: A Prospective, Double-blind Trial.

BACKGROUND This prospective, double-blind study investigated the clinical diagnostic value of synovial fluid S100 calcium-binding protein A8 (S100A8) and S100 calcium-binding protein A9 (S100A9) in periprosthetic joint infection (PJI) and investigated the subtypes of a-defensin that have diagnostic value for PJI. MATERIAL AND METHODS Synovial fluid samples were collected from 82 patients with suspected PJI after total joint arthroplasty. Patients were divided into a PJI group (n=39) and non-PJI group (n=43). Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used to determine S100A8, S100A9, alpha-defensin, and internal reference standards in synovial fluid. The receiver operating characteristic (ROC) curve was used to analyze the diagnostic efficiency of S100A8, S100A9, and alpha-defensin for PJI, as well as the diagnostic value in combination with common biomarkers of infection. RESULTS S100A8, 3 variants of S100A9, and 3 alpha-defensins (human neutrophil peptides [HNP]1-3) in synovial fluid were significantly higher in the PJI group than in the non-PJI group (P<0.001). The sensitivity, specificity, and the area under ROC curve (AUC) for diagnosing PJI were 97.4%, 86.0%, and 0.964 (95% CI: 0.929-0.998), respectively, for synovial fluid S100A8; 87.2%, 88.4% and 0.902 (95% CI: 0.823-0.980), respectively, for S100A9; and 89.7%, 83.7%, and 0.933 (95% CI: 0.884-0.982), respectively, for HNP1-3. The diagnostic efficiency was improved when combined with synovial fluid white blood cell count and percentage of polymorphonuclear neutrophils. CONCLUSIONS Synovial fluid S100A8, S100A9, and HNP1-3 have satisfactory diagnostic efficiency for the diagnosis of PJI, which will help clinicians to accurately diagnose PJI.

Discovery of a 2,6-diarylpyridine-based hydroxamic acid derivative as novel histone deacetylase 8 and tubulin dual inhibitor for the treatment of neuroblastoma.

Herein, two series of HDAC/tubulin dual inhibitors via introducing the key pharmacophore of HDAC inhibitor into the skeletons of 2,6-diarylpyridine and 2'-arylchalcone were synthesized. Among them, 2,6-diarylpyridine-based hydroxamic acid 10a exhibited good inhibitory activity against HDAC8 (IC50 = 117 nM) with 50-fold and 42-fold high selectivity relative to HDAC1 and HDAC6, respectively. Meanwhile, 10a disrupted tubulin polymerization effectively and exhibited potent antiproliferative activity against BE-(2)-C cell line, with IC50 value of 17 nM. Mechanism studies revealed that 10a blocked cell cycle, induced cellular apoptosis and suppressed colony formation. Moreover, 10a possessed good physicochemical properties and metabolic stability. Importantly, 10a exhibited better antitumor effects in human neuroblastoma xenograft mice model than those of clinical HDAC inhibitor and tubulin inhibitor, whether used alone or in combination. These results highlighted the advantages of the HDAC8/tubulin dual inhibitor 10a as an outstanding antitumor agent.

Simultaneous determination of inflammatory factors SAA and LTF based on stable element labeling and inductively coupled plasma mass spectrometry to aid in the diagnosis of infection.

OBJECTIVE: The clinical value of Serum amyloid A (SAA) and Lactoferrin (LTF) has received significant attention, but their detection methods are inadequate, which limits their application. This study aims to develop a dual detection method based on stable element labeling strategies and inductively coupled plasma mass spectrometry (ICP-MS) for SAA/LTF and to assess whether it can be widely used in clinical practice. METHODS: A duplex immunoassay system based on sandwich method was constructed. After optimization, methodological evaluation was performed with the guidelines of Clinical Laboratory Standards Institute (CLSI). Finally, 131 plasma samples were collected to analyze whether the new method is suitable for clinical detection. RESULTS: The LoB, LLoQ, ULoQ, and linear range of the assay were 1.09 ng/mL, 3 ng/mL, 1500 ng/mL, 3-1500 ng/mL for SAA and 0.85 ng/mL, 2 ng/mL, 1200 ng/mL, 2-1200 ng/mL for LTF respectively. The recovery rates were 95.01% to 106.26%, the intra-batch precision of low, intermediate, and high-level samples was <8%, and the inter-batch of them was <11%, the deviation of interference test results was less than±10%. The Area Under the Curve (AUC) was 0.9809 for SAA, 0.8599 for LTF, and 0.9986 for combination. CONCLUSION: The quantitative duplex immunoassay for SAA/LTF has high accuracy, good precision, and high specificity, which meets the clinical testing requirements and can be widely used in clinical practice.

Delayed intestinal perforation associated with peritoneal dialysis: A case report of maintaining dialysis after perforation.

Delayed intestinal perforation has various manifestations. For peritonitis with delayed treatment and multi-bacterial peritonitis, we should be alert to the occurrence of this rare complication. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis. Delayed intestinal perforation of peritoneal dialysis catheter is a rare but serious complication. We reported a 49-year-old patient who had been hospitalized twice within 3 months due to poor drainage of the peritoneal dialysis catheter. During the first hospitalization, peritoneal dialysis-related peritonitis was diagnosed, and a variety of bacterial infections were cultivated. However, at that time, the actual peritoneal dialysis catheter-related intestinal perforation was missed, and he was discharged after anti-infection treatment until a clinical cure was met. After more than 2 months of normal peritoneal dialysis after returning home, the patient again had poor drainage of the peritoneal dialysis catheter, accompanied by the outflow of yellowish-brown sediment. It was found that the peritoneal dialysis catheter had evidence of intestinal perforation. After the removal of the catheter and intestinal repair, he recovered and was discharged from the hospital and received long-term hemodialysis treatment. In the case of delayed intestinal perforation, peritoneal dialysis was maintained normally for more than 2 months, which was an unprecedented situation in previous case reports. In addition, we should be alert to the occurrence of this rare complication, especially when we find the occurrence of polybacterial Peritonitis. Abdominal CT examination and imaging results judgment based on clinical conditions are particularly important for diagnosis.

Circ-USP9X accelerates deep vein thrombosis after fracture by acting as a miR-148b-3p sponge and upregulates SRC kinase signaling inhibitor 1.

OBJECTIVES: This study aims to elucidate the role of circUSP9X (Circular RNA Ubiquitin Specific Peptidase 9 X-Linked) in the development of venous thrombosis in the lower extremities. METHODS: An animal model of Deep Vein Thrombosis (DVT) and a hypoxic model of Human Umbilical Vein Endothelial Cells (HUVECs) treated with Cobalt (II) Chloride (CoCl2) were developed. The expression levels of circUSP9X, microRNA-148b-3p (miR-148b-3p), and SRC Kinase Signaling Inhibitor 1 (SRCIN1) were quantified using quantitative reverse transcription Polymerase Chain Reaction and Western blot analysis. Cell cytotoxicity, viability, apoptosis, and inflammation in HUVECs were assessed via Lactate Dehydrogenase (LDH) assay, MTT assay, flow cytometry, Enzyme-Linked Immunosorbent Assay, and Western blot, respectively. Hematoxylin and Eosin staining were employed for histopathological examination of the venous tissues in the animal model. The interaction between circUSP9X, miR-148b-3p, and SRCIN1 was further explored through dual-luciferase reporter assays and RNA Immunoprecipitation experiments. RESULTS: The present findings reveal a significant upregulation of circUSP9X and SRCIN1 and a concurrent downregulation of miR-148b-3p in DVT cases. Knockdown of circUSP9X or overexpression of miR-148b-3p ameliorated CoCl2-induced apoptosis in HUVECs, reduced LDH release, enhanced cellular viability, and mitigated inflammation. Conversely, overexpression of circUSP9X intensified CoCl2's cytotoxic effects. The effects of manipulating circUSP9X expression were counteracted by the corresponding modulation of miR-148b-3p and SRCIN1 levels. Additionally, circUSP9X knockdown effectively inhibited the formation of DVT in the mouse model. A competitive binding mechanism of circUSP9X for miR-148b-3p, modulating SRCIN1 expression, was identified. CONCLUSION: circUSP9X promotes the formation of DVT through the regulation of the miR-148b-3p/SRCIN1 axis.

Desorption of bis(2-chloroethyl) sulfide, mustard agent, from the surface of hardened cement paste (HCP) wafers.

The decontamination of surfaces exposed to chemical warfare agents is an interesting scientific topic. The desorption behavior of bis(2-chloroethyl) sulfide (sulfur mustard, HD) from the surface of the HD-contaminated hardened cement paste (HCP) was investigated under different weather conditions, which should provide scientific reference data for protection and decontamination projects involving HD-contaminated HCP in different conditions. The desorption of HD from the surface of HCP wafers was studied, and the effects of the purge air flow rate, water content, sorption temperature, and substrate age were investigated. HD desorption was detected from the surface of HD-contaminated HCP, but the desorption velocity was relatively slow. The desorption quantity remained within an order of magnitude throughout a time span of 36h (25°C at 200mL/min of purge air), and the amount of HD that was desorbed from each square meter of HCP surface was approximately 1.1g (25°C at 200mL/min of purge air), which was approximately 5.5 percent of the total HD that was initially applied. A higher flow rate of the purge air, increased water content, and longer substrate age of HCP all increased the HD desorption. In contrast, increased temperatures suppressed HD desorption.

Structural Modification and Pharmacological Evaluation of Substituted Quinoline-5,8-diones as Potent NSD2 Inhibitors.

The histone lysine methyltransferase NSD2 is overexpressed, translocated, or mutated in multiple types of cancers and has emerged as an attractive therapeutic target. However, the development of small-molecule NSD2 inhibitors is still in its infancy, and selective and efficacious NSD2 inhibitors are highly desirable. Here, in view of the structural novelty of the reported NSD2 inhibitor DA3003-1, we conducted a comprehensive structural optimization based on the quinoline-5,8-dione scaffold. Compound 15a was identified possessing both high NSD2 inhibitory activity and potent anti-proliferative effects in the cell. Meanwhile, compound 15a has an excellent pharmacokinetic profile with high oral bioavailability. Further, this compound was found to display significant antitumor efficacy with desirable safety profile in the multiple myeloma xenograft mice models, thus warranting it as a promising candidate for further investigation.

Catalytic ozonation of multi-VOCs mixtures over Cr-based bimetallic oxides catalysts from simulated flue gas: Effects of NO/SO2/H2O.

Different Cr-based bimetallic oxides were prepared, and their catalytic performance was evaluated on the simultaneous removal of multi-VOCs mixtures (acetone, benzene, toluene, and o-xylene) by ozonation. Among them, Co-Cr catalyst stood out in catalytic ozonation of aromatic VOCs, and its activity on acetone conversion was promoted by raising the temperature and ozone concentrations, owing to lower crystallization, larger surface area, excellent redox and VOCs/CO2 desorption ability. Above 95% conversion of all multi-VOCs was achieved over the Co-Cr catalyst when the temperature was 100 °C and an excess ozone ratio λ (the ratio of actual moles of ozone to theoretical moles of ozone needed) was equal to 3. A competitive relationship was noticed during the removal process of four multiple VOCs, with significant inhibition of acetone conversion in the presence of aromatic VOCs, conceivably due to adsorption competition and byproducts accumulation. Effects of NO/SO2/H2O and respective reversibility were also investigated. The inhibition effects of NO/SO2/H2O on aromatic VOCs were far less than those on acetone. Further, the retarding effect of NO was reversible, attributing to physical adsorption competition, but the inhibition effect of SO2/H2O was irreversible, due to the blockage of active sites for VOCs removal. With the combination of scrubbing, multi-VOCs and NO/SO2 could be removed by catalytic ozonation simultaneously and efficiently. In-situ DRIFTS measurement was also conducted to investigate the adsorption and catalytic ozonation process of multi-VOCs mixtures, as well as under the presence of SO2/H2O, discovering the major intermediates, surface carboxylates and carboxylic acids.

Catalytic Decomposition of Residual Ozone over Cactus-like MnO2 Nanosphere: Synergistic Mechanism and SO2/H2O Interference.

Ground-level ozone is an irritant and is harmful to human respiratory and nervous systems. Thus, four manganese oxides with different crystals were hydrothermally synthesized to decompose residual ozone (deO3) in an ozone synergistic-oxidation system. Among them, a cactus-like MnO2-IV nanosphere exhibited the highest deO3 activity, with excellent tolerance to water vapor and SO2/H2O, which could maintain >88% deO3 efficiency in the high-humidity and sulfur-containing conditions. It benefits from the unique morphology, high specific surface area, superior redox properties, oxygen chemisorption capabilities, abundant surface-active hydroxyl species, and low valence Mn species. More importantly, the detailed interference mechanism of O2/O3/H2O/SO2 molecules on MnO2-IV was revealed utilizing in situ diffused reflectance infrared Fourier transform spectroscopy and X-ray photoelectron spectroscopy. H2O generally caused recoverable deactivation, but that caused by SO2 was irreversible. The synergistic effect of SO2/H2O promoted the formation of an unstable sulfate species, thereby deepening the deactivation but inhibiting the irreversible poisoning. Finally, nine specific steps to decompose ozone via surface-active hydroxyl/intermediates were established.

Piezo-Type Mechanosensitive Ion Channel Component 1 (Piezo1): A Promising Therapeutic Target and Its Modulators.

Piezo1 is a member of the mechanosensitive piezo ion channel family, which transduces various mechanical stimulations into electrochemical signals. Piezo1 is closely implicated in different physiological processes ranging from erythrocyte volume homeostasis to lymphatic vessel formation and bone homeostasis. Aberrant Piezo1 functions caused by gain-of-function or loss-of-function mutations are associated with various pathological conditions. Due to the significant contribution on the recognition of Piezo ion channels for sensing mechanical stress, Ardem Patapoutian received the 2021 Nobel Prize in Physiology or Medicine (jointly). Strategies of targeting and modulating Piezo1 have shown potential to produce significant therapeutic effects, thus validating Piezo1 as a promising drug target for diseases. In this Perspective, we review the cryo-EM structure, mechanogating mechanism, and physiological profiles of Piezo1, together with the latest advances in the development of its modulators. Limitations and challenges as well as future development of Piezo1 modulators are discussed as well.

Bifunctional chiral selenium-containing 1,4-diarylazetidin-2-ones with potent antitumor activities by disrupting tubulin polymerization and inducing reactive oxygen species production.

Organoselenium compounds have attracted growing interests as promising antitumor agents over recent years. Herein, four series of novel selenium-containing chiral 1,4-diarylazetidin-2-ones were asymmetrically synthesized and biologically evaluated for antitumor activities. Among them, compound 7 was found to be about 10-fold more potent than its prototype compound 1a, and compound 9a exhibited the most potent cytotoxicity against five human cancer cell lines, including a paclitaxel-resistant human ovarian cancer cell line A2780T, with IC50 values ranging from 1 to 3 nM. Mechanistic studies revealed that compound 9a worked by disrupting tubulin polymerization, inducing reactive oxygen species (ROS) production, decreasing mitochondrial membrane potential, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis and suppressing angiogenesis. Additionally, compound 9a exhibited appropriate human-microsomal metabolic stability and physicochemical properties. Importantly, compound 9a was found to inhibit tumor growth effectively in a xenograft mice model with low toxicity profile, which rendered 9a a highly promising candidate for further pre-clinical development.

Teleost CD4+ helper T cells: Molecular characteristics and functions and comparison with mammalian counterparts.

CD4+ helper T cells play key and diverse roles in inducing adaptive immune responses in vertebrates. The CD4 molecule, which is found on the surfaces of CD4+ helper T cells, can be used to distinguish subsets of helper T cells. Teleosts are the oldest living species with bona-fide CD4 coreceptors. Although some components of immune systems of teleosts and mammals appear to be similar, many physiological differences are represented between them. Previous studies have shown that two CD4 paralogs are present in teleosts, whereas only one is present in mammals. Therefore, in this review, the CD4 molecular structure, expression profiles, subpopulations, and biological functions of teleost CD4+ helper T cells were summarized and compared with those of their mammalian counterparts to understand the differences in CD4 molecules between teleosts and mammals. This review provides suggestions for further studies on the CD4 molecular function and regulatory mechanism of CD4+ helper T cells in teleost fish and will help establish therapeutic strategies to control fish diseases in the future.

Progressive osseous heteroplasia: a case report and literature review.

OBJECTIVE: To investigate the clinical features and pathogenesis of progressive osseous heteroplasia (POH) in children. METHODS: The clinical features and imaging findings of a child with POH are described, and family investigations and gene comparisons were performed, followed by a literature review. RESULTS: A 9-year-old female with no relevant family medical history initially presented with ectopic ossification of the skin and subcutaneous tissue of the right face that developed slowly. The ossification area extended to the right waist, back, and right knee. The unilateral body (limbs) was gradually invaded. The patient exhibited limited movement of the head, neck, and left shoulder joint, and experienced difficulty in opening her mouth. She also exhibited deformity of the toe, delayed development, insufficient language skills and behavioral ability, and difficulty in communicating with others, but had no apparent endocrine disorders. Blood calcium, phosphorus, and alkaline phosphatase levels were normal, and DNA sequencing did not yield a positive result. CONCLUSION: The clinical manifestations of POH include hard plaques, which can develop deep into the bone; however, there are currently no effective preventive or treatment measures.

Discovery of a chiral fluorinated azetidin-2-one as a tubulin polymerisation inhibitor with potent antitumour efficacy.

Inhibition of tubulin polymerisation with small molecules has been clinically validated as a promising therapy for multiple solid tumours. Herein, a series of chiral azetidin-2-ones were asymmetrically synthesised and biologically evaluated for antitumour activities. Among them, a chiral fluorinated azetidin-2-one, 18, was found to exhibit the most potent activities against five cancer cell lines, including a drug-resistant cell line, with IC50 values ranging from 1.0 to 3.6 nM. Further mechanistic studies revealed that the compound 18 worked by disrupting tubulin polymerisation, blocking the cell cycle in the G2/M phase, inducing cellular apoptosis, and suppressing angiogenesis. Additionally, 18 exhibited higher human-microsomal metabolic stability and aqueous solubility compared to those of combretastatin A-4. Finally, 18 was also found to effectively inhibit tumour growth in a xenograft mice model with low toxicity and thus might be a promising lead for further clinical development.